MITOSTATIN, a putative tumor suppressor on chromosome 12q24.1, is downregulated in human bladder and breast cancer.
Allelic deletions on human chromosome 12q24 are frequently reported in a variety of malignant neoplasms, indicating the presence of a tumor suppressor gene(s) in this chromosomal region. However, no reasonable candidate has been identified so far. In this study, we report the cloning and functional characterization of a novel mitochondrial protein with tumor suppressor activity, henceforth designated MITOSTATIN. Human MITOSTATIN was found within a 3.2-kb transcript, which encoded a approximately 62 kDa, ubiquitously expressed protein with little homology to any known protein. We found homozygous deletions and mutations of MITOSTATIN gene in approximately 5 and approximately 11% of various cancer-derived cells and solid tumors, respectively. When transiently overexpressed, MITOSTATIN inhibited colony formation, tumor cell growth and was proapoptotic, all features shared by established tumor suppressor genes. We discovered a specific link between MITOSTATIN overexpression and downregulation of Hsp27. Conversely, MITOSTATIN knockdown cells showed an increase in cell growth and cell survival rates. Finally, MITOSTATIN expression was significantly reduced in primary bladder and breast tumors, and its reduction was associated with advanced tumor stages. Our findings support the hypothesis that MITOSTATIN has many hallmarks of a classical tumor suppressor in solid tumors and may play an important role in cancer development and progression.
Vecchione
A
A
Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Fassan
M
M
Anesti
V
V
Morrione
A
A
Goldoni
S
S
Baldassarre
G
G
Byrne
D
D
D'Arca
D
D
Palazzo
J P
JP
Lloyd
J
J
Scorrano
L
L
Gomella
L G
LG
Iozzo
R V
RV
Baffa
R
R
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins; D002455:Cell Division / Q000235:genetics; D045744:Cell Line, Tumor / Q000378:metabolism / Q000648:ultrastructure; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D003001:Cloning, Molecular; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D055551:HSP27 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics; D006360:Heat-Shock Proteins; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013045:Species Specificity; D014410:Tumor Stem Cell Assay; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
D002352:Carrier Proteins; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011993:Recombinant Fusion Proteins; C502303:TCHP protein, human; D025521:Tumor Suppressor Proteins